The present invention relates to 2-oxobicyclo[3.1.0]hexane-6-carboxylic acid derivatives and to a process for producing the same.
The metabotropic glutamate receptors, which correspond to one type of glutamate receptors, are classified pharmacologically into three groups. Of these, those in group 2 (mGluR2/mGluR3) bind with adenylcyclase and inhibit the accumulation of the Forskolin stimulation of cyclic adenosine monophosphate (CAMP) (Trends Pharmacol. Sci., 14, 13 (1993)), and for this reason, it is suggested that the compounds acting on group 2 metabotropic glutamate receptors have treatment effects and prevention effects on psychiatric disorders such as, for example, schizophrenia, anxiety and its associated diseases, depression, bipolar disorder, and epilepsy; and on neurological diseases such as drug dependence, cognitive disorders, Alzheimer""s disease, Huntington""s chorea, Parkinson""s disease, dyskinesia associated with muscular rigidity, cerebral ischemia, cerebral failure, myelopathy, and head trauma.
The present inventors discovered 2-amino-4-oxobicyclo[3.1.0]hexane-2,6-dicarboxylic acid (7) as one of the useful compounds acting on group 2 metabotropic glutamate receptors (Japanese Patent Application No. Hei 10-246344). In the specification of Japanese Patent Application No. Hei 10-246344, as a preparation method thereof, a synthesis method as described below is proposed. The synthesis method comprises the steps of adding benzyl alcohol to an enone derivative (8) to yield a benzyloxy compound (9), subsequently subjecting the compound (9) to hydantoination to yield a hydantoin derivative (10), subsequently subjecting the derivative (10) to debenzylation, oxidation, and thioketalation to yield a thioketal-hydantoin derivative (11), followed by hydrolysis (in the reaction schemes described below, R2, R3, and R5 are identical or different, each represents a lower alkyl group having 1 to 10 carbon atoms, with the proviso that R2 and R3 together may represent xe2x80x94(CH2)nxe2x80x94 (wherein n represents 2 or 3)). 
An objective of the present invention is to provide novel intermediates which are useful for efficient synthesis of 2-amino-4-oxobicyclo[3.1.0]hexane-2,6-dicarboxylic acid acting on group 2 metabotropic glutamate receptors, which has treatment effects and prevention effects on psychiatric disorders such as schizophrenia, anxiety and its associated diseases, depression, bipolar disorder, and epilepsy, and neurological disorders such as drug dependence, cognitive disorders, Alzheimer""s disease, Huntington""s chorea, Parkinson""s disease, dyskinesia associated with muscular rigidity, cerebral ischemia, cerebral failure, myelopathy, and head trauma, and a process for producing the same.
As a result of diligent research, the present inventors discovered that a 2-oxobicyclo[3.1.0]hexane-6-carboxylic acid derivative (1), which may be synthesized using, as a starting material, 4-hydroxy-2-cyclopentenone, or the hydroxy-group-protected compound thereof, which is easily derived from furfuryl alcohol, is useful for an efficient synthesis of 2-amino-4-oxobicyclo[3.1.0]hexane-2,6-dicarboxylic acid (7), and completed the present invention.
That is, one mode of the present invention corresponds to a 2-oxobicyclo[3.1.0]hexane-6-carboxylic acid derivative represented by formula (1) 
[wherein, R1 represents a hydrogen atom, a C1-C6 alkyl group, a C3-C6 cycloalkyl group, a C3-C6 cycloalkyl C1-C6 alkyl group, an aryl group, an aryl C1-C6 alkyl group, a C1-C6 alkoxy C1-C6 alkyl group, a C1-C6 hydroxyalkyl group, a C1-C6 alkylthio C1-C6 alkyl group, a C1-C6 mercaptoalkyl group, a tetrahydrofuranyl group, or a tetrahydropyranyl group; R2 and R3 are identical or different, and each represents a C1-C6 alkyl group, a C3-C6 cycloalkyl group, a C3-C6 cycloalkyl C1-C6 alkyl group, an aryl group, or an aryl C1-C6 alkyl group, or alternatively, R2 and R3 together represent xe2x80x94(CH2)nxe2x80x94 (wherein n represents 2 or 3); and Y1 and Y2 are identical or different, and each represents a sulfur atom, an oxygen atom, or a nitrogen atom].
In addition, another mode of the present invention corresponds to a process for producing a 2-oxobicyclo[3.1.0]hexane-6-carboxylic acid derivative (1), comprising the steps of:
reacting a cyclopentenone derivative represented by formula (2) 
[wherein, R4 represents a hydrogen atom or a protecting group of the hydroxyl group]
with a sulfonium ylide represented by Me2Sxe2x95x90CHCO2R5 [wherein, R5 represents a C1-C6 alkyl group, a C3-C6 cycloalkyl group, a C3-C6 cycloalkyl C1-C6 alkyl group, an aryl group, an aryl C1-C6 alkyl group, a C1-C6 alkoxy C1-C6 alkyl group, a C1-C6 hydroxyalkyl group, a C1-C6 alkylthio C1-C6 alkyl group, a C1-C6 mercaptoalkyl group, a tetrahydrofuranyl group, or a tetrahydropyranyl group] or alternatively, with a sulfonium salt represented by Me2S+CH2CO2R5.Xxe2x88x92 [wherein, R5 is the same as described above; and X represents a chlorine atom, a bromine atom, or an iodine atom]
to yield a bicyclo compound represented by formula (3) 
[wherein, R4 and R5 are the same as described above];
protecting the carbonyl group of said bicyclo compound to yield a derivative represented by formula (4) 
[wherein, R2 and R3 are identical or different, and each represents a C1-C6 alkyl group, a C3-C6 cycloalkyl group, a C3-C6 cycloalkyl C1-C6 alkyl group, an aryl group, or an aryl C1-C6 alkyl group, or alternatively, R2 and R3 together represent xe2x80x94(CH2)nxe2x80x94 (wherein n represents 2 or 3); Y1 and Y2 are identical or different, and each represents a sulfur atom, an oxygen atom, or a nitrogen atom; and R4 and R5 are the same as described above]; and
oxidizing said derivative wherein R4 represents a hydrogen atom, with the proviso that in the case of R4 of said derivative representing a group other than a hydrogen atom, the R4 is converted into a hydrogen atom beforehand.
Furthermore, another mode of the present invention corresponds to a bicyclo[3.1.0]hexane-6-carboxylic acid derivative, which may be derived from the carboxylic acid derivative (1), represented by formula (5) 
[wherein, R1 represents a hydrogen atom, a C1-C6 alkyl group, a C3-C6 cycloalkyl group, a C3-C6 cycloalkyl C1-C6 alkyl group, an aryl group, an aryl C1-C6 alkyl group, a C1-C6 alkoxy C1-C6 alkyl group, a C1-C6 hydroxyalkyl group, a C1-C6 alkylthio C1-C6 alkyl group, a C1-C6 mercaptoalkyl group, a tetrahydrofuranyl group, or a tetrahydropyranyl group; R2 and R3 are identical or different, and each represents a C1-C6 alkyl group, a C3-C6 cycloalkyl group, a C3-C6 cycloalkyl C1-C6 alkyl group, an aryl group, or an aryl C1-C6 alkyl group, or alternatively, R2 and R3 together represent xe2x80x94(CH2)nxe2x80x94 (wherein n represents 2 or 3); and Y1 and Y2 are identical or different, and each represents a sulfur atom, an oxygen atom, or a nitrogen atom].
The terms used in the present invention are defined in the following. In the present invention, xe2x80x9cCn-Cmxe2x80x9d means that the group following the xe2x80x9cCn-Cmxe2x80x9d has from n to m carbon atoms.
The C1-C6 alkyl group means a straight-chain or branched-chain alkyl group having 1 to 6 carbon atoms, examples of which include, for example, a methyl group, an ethyl group, a propyl group, an isopropyl group, a butyl group, an isobutyl group, a t-butyl group, a pentyl group, an isopentyl group, a hexyl group, an isohexyl group, and the like.
The C3-C6 cycloalkyl group means a cyclic alkyl group having 3 to 6 carbon atoms, examples of which include, for example, a cyclopropyl group, a cyclopentyl group, a cyclohexyl group, or the like.
The C3-C6 cycloalkyl C1-C6 alkyl group means a group having a combined structure of a C3-C6 cycloalkyl group and a C1-C6 alkyl group, examples of which include, for example, a cyclopropylmethyl group, a cyclobutylmethyl group, a cyclopentylmethyl group, a cyclohexylmethyl group, and the like.
The aryl group means a phenyl group, a naphthyl group, or the like, and is preferably a phenyl group. The aryl C1-C6 alkyl means a straight-chain or branched-chain alkyl group having 1 to 6 carbon atoms, substituted with at least one aryl group, and preferably a phenyl group. Examples thereof include, for example, a benzyl group, a diphenylmethyl group, a 1-phenylethyl group, a 2-phenylethyl group, and the like.
The C1-C6 alkoxy C1-6 alkyl group means a group having a combined structure of a C1-6 alkoxy group and a C1-6 alkyl group. The C1-C6 alkoxy group means a straight-chain or branched-chain alkoxy group having 1 to 6 carbon atoms, examples of which include, for example, a methoxy group, an ethoxy group, a propoxy group, an isopropoxy group, a butoxy group, an isobutoxy group, a t-butoxy group, a pentyloxy group, an isopentyloxy group, or the like. Therefore, examples of the C1-C6 alkoxy C1-C6 alkyl groups include a methoxymethyl group, an ethoxymethyl group, a methoxyethyl group, an ethoxyethyl group, a propoxyethyl group, an isopropoxyethyl group, a butoxyethyl group, an isobutoxyethyl group, a pentyloxyethyl group, an isopentyloxyethyl group, and the like.
The C1-C6 hydroxyalkyl group means a C1-6 alkyl group substituted with at least one hydroxyl group. Therefore, examples of the C1-C6 hydroxyalkyl group include, for example, a 2-hydroxyethyl group, a 3-hydroxypropyl group, a 2,3-dihydroxypropyl group, and the like.
The C1-C6 alkylthio C1-C6 alkyl group means a group having a combined structure of a C1-C6 alkylthio group and a C1-C6 alkyl group. The C1-C6 alkylthio group means a straight-chain or branched-chain alkylthio group having 1 to 6 carbon atoms, examples of which include, for example, a methylthio group, an ethylthio group, a propylthio group, an isopropylthio group, a butylthio group, an isobutylthio group, a t-butylthio group, a pentylthio group, an isopentylthio group, and the like. Therefore, examples of the C1-C6 alkylthio C1-C6 alkyl group include a methylthiomethyl group, a 2-methylthioethyl group, and the like.
The C1-C6 mercaptoalkyl group means a C1-C6 alkyl group substituted with at least one mercapto group. Therefore, examples of the C1-C6 mercaptoalkyl group include a 2-mercaptoethyl group, a 3-mercaptopropyl group, a 2,3-dimercaptopropyl group, and the like.
In each group described above, at least one hydrogen atom on the group may be substituted with an atom or with another group, which is not a hydrogen atom, for example, a halogen atom such as a fluorine atom, a chlorine atom, a bromine atom, or an iodine atom; a nitro group; an amino group; a hydroxyl group; a thiol group; a formyl group; a carboxyl group; a cyano group; a carbamoyl group; an alkyl group such as a methyl group, an ethyl group, a propyl group, an isopropyl group, a butyl group, an isobutyl group, a sec-butyl group, a tert-butyl group, a pentyl group, an isopentyl group, a neopentyl group, or a tert-pentyl group; an aryl group and a heterocyclic group such as a phenyl group, a naphthyl group, a biphenyl group, an anthranyl group, a pyrrolyl group, a pyridyl group, or a thienyl group; an alkoxycarbonyl group such as a methoxycarbonyl group, or an ethoxycarbonyl group; an acyl group such as an acetyl group, or a benzoyl group; an alkoxy group such as a methoxy group, an ethoxy group, or a propoxy group; or an alkylthio group such as a methylthio group, an ethylthio group, or a propylthio group. Therefore, for example, a 2,2,2-trichloroethyl group, a phenacyl group, a 2,6-dimethylcyclohexyl group, and a 4-methoxybenzyl group, and the like are also included in the scope of R1 and R2. The number of the carbon atoms in these substituents is not included in the numbers n or m described above.
In the present invention, the protecting group of a hydroxyl group includes protecting groups which are commonly used, such as an acyl group or a trisubstituted silyl group, in addition to the C1-C6 alkyl group, the C3-C6 cycloalkyl group, the C3-C6 cycloalkyl C1-C6 alkyl group, the aryl group, the aryl C1-C6 alkyl group, the C1-C6 alkoxy C1-C6 alkyl group, the C1-C6 hydroxyalkyl group, the C1-C6 alkylthio C1-C6 alkyl group, the Cl-C6 mercaptoalkyl group, the tetrahydrofuranyl group, and the tetrahydropyranyl group, as described above. Here, the acyl group refers to a straight-chain or branched-chain C1-C6 aliphatic or aromatic acyl group. Examples thereof include, for example, an acetyl group, a pivaloyl group, benzoyl group, and the like. In addition, the trisubstituted silyl group refers to a silyl group having three arbitrary substituents selected from an alkyl group having 1 to 6 carbon atoms and a phenyl group. Examples thereof include, for example, a trimethylsilyl group, a triethylsilyl group, a tert-butyldimethylsilyl group, a tert-butyldiphenylsilyl group, and the like.
In the compounds represented by formula (1), in the case where R2xe2x80x94Y1xe2x80x94 and R3xe2x80x94Y2xe2x80x94 represent the identical group, or in the case where Y1 and Y2 are identical and R2 and R3 together represent xe2x80x94(CH2)nxe2x80x94 (wherein n represents 2 or 3), three asymmetric carbon atoms are present at the 1-position, 5-position, and 6-position. In addition, in the case where Y1 or Y2, or alternatively, R2 or R3 is different, four asymmetric carbon atoms are present at the 1-position, 4-position, 5-position, and 6-position. Therefore, the compounds of the present invention may be present as optically active substances, enantiomer mixtures such as racemic bodies, or diastereomer mixtures. That is, the compounds of the present invention include all of the optically active substances, the enantiomer mixtures such as racemic bodies, and the diastereomer mixtures, of the compounds represented by formula (1).